BACKGROUND:Epithelial ovarian cancer frequently recurs and becomes resistant to platinum chemotherapy. We investigated whether adding pembrolizumab to weekly paclitaxel, with or without bevacizumab, improves progression-free survival and overall survival compared with weekly paclitaxel, with or without bevacizumab, in participants with platinum-resistant recurrent ovarian cancer who had received one to two previous systemic regimens. METHODS:ENGOT-ov65/KEYNOTE-B96 is a randomised, double-blind, phase 3 study conducted at 187 gynaecologic oncology centres in 25 countries in the Americas, Asia, Europe, and Oceania. Adults (≥18 years) with histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, who received one to two previous systemic therapies including at least one platinum regimen and who progressed 6 months or less after the last platinum regimen, were eligible. Participants were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle or intravenous placebo (saline solution) every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle; intravenous bevacizumab 10 mg/kg every 2 weeks was permitted per investigator. Randomisation was stratified by planned bevacizumab use, region, and PD-L1 combined positive score (CPS). The primary endpoint was investigator-assessed progression-free survival per RECIST version 1.1; the key secondary endpoint was overall survival. Results from two interim analyses and the final analysis are included in this Article. This study is registered with ClinicalTrials.gov, NCT05116189, and is now completed. FINDINGS:Between Dec 13, 2021, and July 3, 2023, 643 female participants were randomly assigned; 322 to pembrolizumab plus paclitaxel and 321 to placebo plus paclitaxel. At the first interim analysis, pembrolizumab plus paclitaxel significantly improved progression-free survival versus placebo plus paclitaxel in both the PD-L1 CPS 1 or higher (median 8·3 months vs 7·2 months; hazard ratio [HR] 0·72; 95% CI 0·58-0·89; p=0·0014 α=0·012]) and overall populations (median 8·3 months vs 6·4 months; HR 0·70, 95% CI 0·58-0·84; p<0·0001, [α=0·0023]), meeting the prespecified criteria for confirmatory efficacy. At the second interim analysis, overall survival was significantly improved in the PD-L1 CPS 1 or higher population (median 18·2 months vs 14·0 months; HR 0·76, 95% CI 0·61-0·94; p=0·0053, [α=0·0083]). At the final analysis, overall survival was significantly improved in the overall population (median 17·7 months vs 14·0 months; HR 0·82, 95% CI 0·69-0·97; p=0·011 [α=0·024]). Grade 3 or worse treatment-related adverse events occurred in 217 (68%) of 320 participants in the pembrolizumab plus paclitaxel group versus 176 (55%) of 318 participants in the placebo plus paclitaxel group. The most common treatment-related adverse events (any grade) included anaemia, peripheral neuropathy, alopecia, fatigue, and nausea. Treatment-related adverse events resulted in death in four participants (1%) in the pembrolizumab plus paclitaxel group (colitis, interstitial lung disease, acute myeloid leukaemia, and intestinal perforation) and in five participants (2%) in the placebo plus paclitaxel group (cardiac failure, intestinal perforation [in two participants], and large-intestine perforation [in two participants]). INTERPRETATION:Pembrolizumab plus weekly paclitaxel, with or without bevacizumab, significantly improved progression-free survival and overall survival in participants with platinum-resistant recurrent ovarian cancer who had received one to two previous systemic regimens, supporting this regimen as a new treatment option for this population. FUNDING:Funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

We aimed to explore the diagnostic value of [18F]F-NOTA-FAPI-FUSCC-07 ([18F]F-NOTA-FAPI) PET/CT in suspected recurrence ovarian cancer with CA125 dynamic rising but negative conventional imaging findings. Forty-one suspected recurrent ovarian cancers who experienced [18F]F-NOTA-FAPI PET/CT for further diagnosis because of continuously rising CA125 value but negative conventional imaging (CT, MR or [18F]FDG PET/CT) findings were enrolled from June 2022 to January 2024. All conventional and [18F]F-FAPI PET/CT scans were performed in sequence within one week. Clinical characteristics, treatment data, [18F]F-NOTA-FAPI PET/CT findings, and survival outcomes were recorded. Differences in [18F]F-NOTA-FAPI PET/CT parameters across CA125 levels were analyzed using the Mann-Whitney U test. [18F]F-NOTA-FAPI PET/CT was positive in 34 patients (82.93

To prospectively explore efficacy and safety of radiotherapy combined with albumin-bound paclitaxel and platinum-based chemotherapy for locoregional recurrent cervical cancer (CC). Patients with locoregional recurrent CC were enrolled in the analysis. The enrolled patients received radiotherapy and albumin-bound paclitaxel and platinum-based chemotherapy. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and safety. 99 patients were enrolled. For all patients, the 3-year PFS and 3-year OS were 48.5

BackgroundOvarian clear cell carcinoma (OCCC) is a rare aggressive, and chemo-resistant subtype of epithelial ovarian cancer. Current limitations in precisely characterizing its molecular features have resulted in restricted availability of clinical targeted therapies and significant therapeutic challenges.MethodsTo address this unmet need, we conducted an integrative multi-omics study of 82 OCCC cases, incorporating whole-exome sequencing (WES), bulk RNA sequencing, and single-cell RNA sequencing (scRNA-seq).ResultsOur analysis uncovered recurrent mutations in multiple epigenetic regulators including ARID1A, EP300, and SETD2B, reinforcing chromatin remodeling as a hallmark of OCCC pathogenesis. Strikingly, FOXA2 mutations were absent in early-stage tumors but specifically enriched in advanced-stage cases (19% frequency), with functional validation demonstrating their role in driving malignant progression. Copy number alteration profiling revealed frequent amplifications in chromosomal arms such as 17q, which contains the ERBB2 oncogene that potentially regulates OCCC progression. Chromosomal translocations were detected in 35.59% of cases, including a novel FGFR2/RPAP3 fusion with therapeutic implications. Notably, scRNA-seq delineated immune-rich subsets characterized by abundant cytotoxic T-cell and B-cell infiltration, suggesting immunotherapeutic opportunities in a patient subset. Moreover, molecular subtyping identified ERBB2 amplification/overexpression as a high-risk feature strongly associated with poor survival. Patient-derived xenograft (PDX) models and a retrospective analysis of two clinical cases demonstrated that HER2-targeted antibody-drug conjugates (HER2-ADCs) significantly suppressed tumor growth and progression in OCCC patients with HER2 expression.ConclusionsIn summary, our study establishes the comprehensive molecular atlas and a targeted therapeutic subtyping framework, revealing therapeutic vulnerabilities and providing novel insights for advancing precision oncology in OCCC management.

3026 Background: Treatment options in China are limited for patients with late-line, HER2-expressing advanced solid tumors. In Part 1 of DESTINY-PanTumor02, T-DXd showed clinically meaningful antitumor activity in HER2-expressing advanced solid tumors, with the greatest benefit observed in HER2 IHC 3+ tumors. Based in part on these findings, T-DXd has been approved in multiple countries worldwide, including the US, as treatment for patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior treatment and/or have no satisfactory alternative therapies. Following the results from DESTINY-PanTumor02, DESTINY-PanTumor03 is evaluating T-DXd in patients in China with HER2-expressing advanced solid tumors. The primary analysis of Part 1 of DESTINY-PanTumor03 is presented here. Methods: DESTINY-PanTumor03 is an open-label, Phase 2 study (NCT06271837). Part 1 is evaluating T-DXd (5.4 mg/kg IV Q3W) in patients in China with HER2 IHC 3+ (by central testing), locally advanced, unresectable, or metastatic solid tumors (excluding breast and gastric cancers) after ≥1 prior systemic treatment for advanced disease or without treatment options. The primary endpoint is confirmed objective response rate (ORR) by independent central review (ICR) per RECIST 1.1. Secondary endpoints include ORR by investigator assessment (INV) per RECIST 1.1; duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) by INV and ICR per RECIST 1.1; overall survival (OS); and safety. Results: At primary analysis data cutoff (November 28, 2025), 50 patients with biliary tract (n = 11), colorectal (n = 6), cervical (n = 10), endometrial (n = 7), ovarian (n = 5), non-small cell lung (n = 7), or other cancers (n = 4) had received T-DXd. Median follow-up duration was 9.9 (range 1.1–18.3) months. Median number of prior treatment regimens was 2 (range 1–10). By ICR, ORR (95% CI) was 58.0% (43.2, 71.8), median DOR (95% CI) was 15.4 (12.5, not evaluable [NE]) months, DCR (95% CI) at Week 6 was 88.0% (75.7, 95.5), and median PFS (95% CI) was 15.7 (7.2, NE) months. By INV, ORR (95% CI) was 56.0% (41.3, 70.0). Median OS was not reached. Grade ≥3 drug-related adverse events occurred in 31 (62.0%) patients, and adjudicated drug-related interstitial lung disease / pneumonitis occurred in 4 (8.0%) patients (Grade 2 n = 3 [6.0%], Grade 3 n = 1 [2.0%]). Conclusions: T-DXd demonstrated durable and clinically meaningful antitumor activity in pretreated patients in China with HER2 IHC 3+ advanced solid tumors. Safety was generally consistent with the established T-DXd profile. Results from DESTINY-PanTumor03 Part 1 support T-DXd as a tumor-agnostic treatment for patients in China with HER2 IHC 3+ solid tumors. Clinical trial information: NCT06271837 .

5579 Background: Patients (pts) with platinum-resistant ovarian cancer (PROC) have a poor prognosis, and traditional cytotoxic drugs have limitations in efficacy and safety. Therefore, we are exploring the combination of utidelone capsule (UTD2), a novel oral microtubule inhibitor, with fruquintinib capsule (F), a tyrosine kinase inhibitor targeting VEGFR 1,2,3, for the treatment of platinum-resistant recurrent ovarian cancer. Methods: This study is an open-label and Simon two-stage phase II clinical trial, aiming to enroll 35 pts with platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. All pts were high-grade serous ovarian cancer, with prior 1-5 lines of systemic therapy, and no more than 3 lines of subsequent therapy after platinum-resistant recurrence. Subjects received F in combination with UTD2 in 21-day cycles. The dose of F was 5 mg once daily, taken orally from day 1 to day 14 of each cycle. The dose of UTD2 was 60 mg/m²/day once daily, taken orally from day 1 to day 5 of each cycle. Primary endpoint was objective response rate (ORR) per RECIST v1.1. In Stage 1, 14 pts received per protocol treatment, and the study would proceed to Stage 2 (enrolling additional 21 patients) if ≥2 objective responses (CR/PR) were observed in Stage 1. Secondary endpoints included investigator-assessed progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), overall survival (OS) and Safety. Results: From March 18, 2025 to December 22, 2025, 19 pts were enrolled. Median age was 59 years (range, 44-68) with an ECOG PS score of 1. Median prior lines systemic therapy was 3 (range, 1-5) with 1, 2, 3, 4 and 5 lines for 4 pts (21.1%), 2 pts (10.5%), 6 pts (31.6%), 5 pts (26.3%), and 2 pts (10.5%), respectively. Median number of chemotherapy lines after platinum resistance was 1 (range, 0-3), with 0, 1, 2, or 3 lines of chemotherapy for 6 pts (31.6%), 6 pts (31.6%), 5 pts (26.3%), and 2 pts (10.5%), respectively. 14 pts were evaluated for efficacy with an outcome of 1 complete response, 8 partial responses and 5 stable diseases. ORR was 64.3% (95% CI: 38.8-83.7) and DCR was 100%. Median PFS was 7 months (95% CI: 2.8-7.2) and median OS has not reached. The Grade 3 treatment-related AE (TRAE) included neutropenia (n=2), mucositis oral (n=1), palmar-plantar erythrodysesthesia syndrome (n=1), skin ulceration (n=1), diarrhea (n=1), pain (n=1) and neurotoxicity (n=1). There were no ≥Grade 4 TRAE. 1 patient discontinued UTD2+F due to TRAEs. Conclusions: Utidelone plus Fruquintinib demonstrated encouraging efficacy for the treatment of PROC with a tolerable safety profile. This study is still actively ongoing, and further data will be provided at time of presentation. Clinical trial information: NCT06973421 .

The molecular subtype of endometrial cancer is important for predicting prognosis and treatment effectiveness. This study aimed to develop an interpretable deep learning model based on H E-stained whole slide images (WSIs) to predict the molecular subtype of endometrial cancer. Data from the Fudan cohort (n = 364) were used to train an end-to-end prediction network for identifying four molecular subtypes. Two external cohorts—the TCGA (n = 296) and Suzhou (n = 36)—were used to validate model generalizability and potential clinical applicability. We further assessed the correlation between histological and molecular features at both the macro- (WSI) and micro- (patch) levels. The network achieved a macro-average area under the receiver operating characteristic curve (AUROC) of 0.867 (95

BACKGROUND:Efficacy of second-line treatments after first-line platinum-based chemotherapy in advanced cervical cancer is modest. This open-label, single-arm, multicentre, proof-of-concept phase 2 study evaluated fruquintinib plus sintilimab in advanced cervical cancer. METHODS:Patients recruited between July 2021 and June 2022 had received at least first-line platinum-based chemotherapy or were unable to receive standard treatment in China. Patients received fruquintinib 5 mg once daily orally (2 weeks on/1 week off) plus sintilimab 200 mg intravenously every 3 weeks. Efficacy and safety analyses included patients who had received at least one dose of study drug. RESULTS:Here we show the results of 34 patients who received treatment; 28 (82%) have prior systemic antitumour therapy, with 19 (68%) pretreated patients having programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1. The objective response rate (ORR) is 32% (95% confidence interval [CI] 17-51), meeting the prespecified effective boundary, and the disease control rate (DCR) is 97% (95% CI 85-100). Median progression-free survival (PFS) and overall survival (OS) are 8.3 months (95% CI 5.5-19.4) and 23.5 months (95% CI 15.8-not estimable [NE]), respectively. The most common grade ≥ 3 treatment-related adverse event is palmar-plantar erythrodysaesthesia syndrome (21%). In pretreated patients with PD-L1 CPS  ≥ 1, ORR is 37% (95% CI 16-62), median PFS is 19.4 months (95% CI 4.0-22.1), and OS rate at 18 months is 72% (95% CI 46-87). CONCLUSIONS:Fruquintinib plus sintilimab may indicate favourable and durable antitumour activity with a manageable safety profile in advanced cervical cancer, especially in pretreated patients with PD-L1 CPS ≥1, warranting further investigation.

Abstract Background: Early detection of gynecologic cancers remains challenging due to nonspecific symptoms and limited sensitivity of conventional biomarkers. We aimed to develop and validate cfDNA-based models for cancer detection and tissue-of-origin (TOO) classification. Methods: We prospectively enrolled 1,007 participants from two hospitals, of whom 763 passed eligibility and quality control. The training set (N=363; 173 cancer, 190 non-cancer) was used to develop models integrating four cfDNA features reflecting fragmentation, chromatin architecture, and epigenetic regulation via machine learning. The internal test set (N=158; 86 cancer, 72 non-cancer) and an independent external test set (N=242; 127 cancer, 115 non-cancer) were used for validation. Results: The diagnostic model achieved area under the curve (AUC) values of 0.974 (95% confidence interval [CI]: 0.954-0.994) and 0.975 (95% CI: 0.959-0.992) in the internal and external cohorts, with sensitivities of 83.7% and 82.7% at 98% specificity. High performance was observed across ovarian (AUC: 0.992 and 0.999), cervical (AUC: 0.972 and 0.989), and endometrial (AUC: 0.948 and 0.937) cancers, including stage I disease (AUC: 0.955 and 0.961). The model detected over 77% of cancers that were missed by CA125. Interception modeling projected a 26.4-68.9% increase in stage I diagnoses and 11.6-37.8% 5-year survival gains. The TOO model achieved >73% overall accuracy, with the highest accuracy for ovarian (81.3-86.7%), followed by cervical (70.7-73.3%) and endometrial (59.1-62.7%) cancers. Analytical validation demonstrated robust performance even at ultra-low sequencing depths of 1x, supporting scalability for population screening. Conclusions: cfDNA fragmentomics enables sensitive detection and tissue-of-origin classification of gynecologic cancers, complementing conventional biomarkers. These models hold promise for cost-effective, population-level early detection and risk stratification. Citation Format: Jin Li, Xun Zhang, Song Wang, Xiaoying Wu, Jinpeng Zhang, Hua Bao, Shanhui Liang, Xiaotian Han, Jiangchun Wu, Hao Wen, Hairong Bao, Haimeng Tang, Xue Wu, Xiaohua Wu, Zhao Wu, Xiaoqiu Li. cfDNA fragmentomics enables sensitive early detection and tissue-of-origin prediction in gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1124.

TPS5645 Background: Despite advancements in frontline therapies for EC, treatment options for recurrent/refractory disease remain limited. HER2 overexpression in EC is associated with rapid disease progression, tumor invasiveness, a high risk of recurrence, and poor prognosis. Trastuzumab pamirtecan (T-Pam; BNT323/DB-1303) is an investigational HER2-targeting antibody-drug conjugate (ADC) with a DNA topoisomerase I inhibitor payload and a drug-to-antibody ratio of ~8. In a phase 1/2a trial (NCT05150691), T-Pam demonstrated encouraging clinical benefit in patients with HER2-expressing EC, efficacy was observed across all HER2 expression levels and patient subgroups with a manageable safety profile. Methods: Following a protocol amendment, this open-label, randomized, multi-site, phase 3 trial (Fern-EC-01; BNT323-01) is enrolling patients with recurrent, HER2 expressing EC (assessed by central laboratory testing using IHC) who have measurable disease defined by RECIST v1.1, an ECOG PS of 0-2, and have received ≥1 prior line of platinum-based therapy (in any setting) and prior immune-checkpoint inhibitor treatment. Up to three lines of prior therapy are permitted. Prior hormonal therapy and radiation are allowed but do not count as prior lines of therapy. Prior exatecan-containing treatment is not allowed. All patients will receive treatment until RECIST v1.1 defined progressive disease, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met. The trial is enrolling two cohorts. In Cohort 1, ≈420 patients with HER2-expressing (IHC 1+ or 2+) EC will be randomized 2:1 to evaluate the efficacy and safety of T-Pam vs investigator’s choice of chemotherapy (doxorubicin, paclitaxel, or docetaxel in case of contraindication to paclitaxel and availability at the site). Stratification is based on HER2 expression (IHC 1+; 2+) and prior lines of therapy (1; 2+). The primary endpoint for Cohort 1 is progression-free survival (PFS) by blinded independent central review (BICR); overall survival is a key secondary endpoint. In Cohort 2, ≈60 patients with HER2 IHC 3+ EC will receive T-Pam; the primary endpoint for this cohort is objective response rate by BICR. Enrollment is ongoing globally. Clinical trial information: NCT06340568 .

MethodsThe study applied a TTE, rigorously defining inclusion criteria, exclusion criteria, treatment strategies and follow-up timepoints to control for selection bias. Participants included newly diagnosed epithelial ovarian cancer patients who underwent radical surgery at Fudan University Shanghai Cancer Center from January 2020 to December 2023. This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (approval number: 2503-Exp155). Inclusion Criteria: ① Pathological type is epithelial ovarian carcinoma; ② Postoperative pathological stage is International Federation of Gynecology and Obstetrics (FIGO) ⅡB to Ⅳ; ③ Age 18 to 75 years; ④ Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1. Exclusion Criteria: ① Preoperative imaging or intraoperative exploration revealed significantly enlarged or suspicious metastatic lymph nodes; ② Surgery did not achieve R0 resection (R0 resection is defined as no macroscopically visible residual tumor within the abdominopelvic cavity); ③ Patients who received neoadjuvant therapy; ④ Patients not receiving first-line treatment for ovarian cancer; ⑤ Postoperative follow-up time less than 3 months. The patients were divided into two groups based on whether lymphadenectomy was performed. Data were derived from the Shanghai Ovarian Cancer Specialized Database and hospital follow-up systems, with a follow-up cutoff date of September 30, 2025. The primary endpoint was overall survival (OS). Survival curves were analyzed using the Kaplan-Meier method, and intergroup differences were evaluated using the log-rank test. Univariate Cox regression was applied to identify factors influencing OS. The significance level was set to α=0.05 for two-tailed tests, with P<0.05 considered statistically significant.ResultsThe study included a total of 353 patients (239 in the no lymphadenectomy group and 114 in the lymphadenectomy group). There were no statistically significant differences between the two groups in baseline characteristics such as age, histological type (both groups had 92.1% high-grade serous carcinoma), FIGO stage (stage Ⅲ: 73.7% vs 74.1%; stage Ⅳ: 17.6% vs 20.2%), genetic mutations ［BRCA1/2 mutation rates and homologous recombination deficiency (HRD) positivity］, surgical procedures, adjuvant chemotherapy and maintenance therapy (all P>0.05). The follow-up period ranged from 3.0 to 54.7 months. OS analysis showed that the 4-year OS rates for the lymphadenectomy group versus the no lymphadenectomy group were 78.4% vs 80.3%, respectively, with no statistically significant difference between groups (P=0.268). Univariate Cox regression analysis showed that age, FIGO stage and lymph node dissection were not significantly associated with OS (all P>0.05).ConclusionIn China, lymphadenectomy maybe offers limited value for patients who have achieved R0 resection and have no evidence of lymph node metastasis during surgery. Its clinical utility requires further validation based on individualized factors, and future multicenter prospective studies should explore its potential role in specific subgroups.Background and purposeThe survival benefit of lymph node dissection in ovarian cancer remains controversial. The LION study, which focused on populations in Europe and the Americas, has yet to demonstrate clear applicability to Chinese patients. This study, based on our hospital's ovarian cancer cohort, employs target trial emulation (TTE) to estimate the real-world clinical value of lymphadenectomy in the Chinese population. It aims to provide localized evidence to optimize surgical strategies and advance personalized precision therapy.

BACKGROUND:Platinum resistance is a major determinant of poor outcome in advanced epithelial ovarian cancer, yet reliable predictors available before treatment initiation remain scarce. Ascitic fluid is commonly obtained during diagnostic work-up and directly reflects the peritoneal tumour microenvironment, but its cytomorphological information has not been systematically exploited for treatment-response prediction. METHODS:We present OVCAP, a multi-scale deep-learning framework that analyses pretreatment ascites cytology whole-slide images to estimate platinum-resistance risk. The study included 438 patients with FIGO stage IIIB-IV epithelial ovarian cancer. Model performance was evaluated in one internal and two independent external validation cohorts. Attention-guided cytopathology review was performed to identify high-risk morphologic patterns, and integrated single-cell RNA sequencing analyses were used to characterise the underlying biological features. RESULTS:OVCAP achieved area under the receiver operating characteristic curve (ROC-AUC) values of 0.894, 0.863, and 0.828 in the internal and two independent external validation cohorts, respectively, and outperformed the KELIM score (AUC 0.619). Attention-guided cytopathology review identified recurrent high-risk morphologic patterns in resistant disease: epithelial cytoplasmic vacuolization and interaction-rich malignant aggregates accompanied by immune and mesothelial cells. Integrated single-cell analyses linked these phenotypes to membrane remodelling, lipid reprogramming, hypoxia-associated stress signalling, and reinforced adhesion and immunoregulatory networks. CONCLUSION:These findings support pretreatment ascites cytology as a clinically accessible substrate for early risk stratification before first-line platinum-based therapy.

Abstract Background: SYN818 is a selective, potent oral POLQ helicase inhibitor. POLQ is essential for microhomology-mediated end-joining and fills single-stranded DNA (ssDNA) gaps during replication. In tumors with homologous recombination repair (HRR) deficiencies (e.g., BRCA1/2 mutations), inhibition of PARP creates a dependency on POLQ for ssDNA gap filling, providing a synthetic lethal therapeutic strategy. Preclinically, SYN818 significantly enhanced the antitumor activity of Olaparib in breast and ovarian cancer models. Phase 1a monotherapy data demonstrate that SYN818 has a favorable pharmacokinetic profile and is well tolerated, supporting further evaluation of SYN818 in combination with Olaparib in HRR-deficient metastatic solid tumors. Trial design: This phase 1b, open-label, multicenter study (NCT07156253; CTR20253189) evaluates SYN818 in combination with Olaparib in adults with locally advanced or metastatic solid tumors harboring BRCA mutations and/or homologous recombination repair (HRR) deficiency. During dose escalation (Part 1), patients receive escalating doses of SYN818 in combination with Olaparib (300 mg BID) administered in 21-day cycles to determine the recommended Phase 2 dose (RP2D), guided by a Bayesian dose-finding model. In the dose-expansion phase (Part 2), tumor-specific cohorts, including ovarian cancer and HER2-negative breast cancer, will further assess safety and preliminary antitumor activity at the RP2D. The primary objectives are to evaluate safety, tolerability, and determine the RP2D. Secondary objectives include characterization of pharmacokinetics, pharmacodynamics, and preliminary antitumor activity per RECIST v1.1. Key eligibility criteria include age ≥18 years, ECOG performance status 0-1, documented BRCA mutation and/or HRR deficiency, and adequate organ function. Prior PARP inhibitor therapy is permitted. Enrollment initiated in September 2025. Citation Format: Hongxia Wang, Xiaohua Wu, Min Yan, Jian Zhang, Youzhong Zhang, Yiqun Du, Sai Han, Xiaojun Liu, Jiajia Li, Limin Niu, Duo Wu, Yue Xie, Xuzhen Tang, Chao Kan, Song Shi, Hu He, Song Liu, Xiaochun Yu. Phase Ib study of POLQ inhibitor SYN818 combined with olaparib in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT289.

BackgroundLymph node metastasis (LNM) is a major prognostic determinant in early-stage cervical squamous cell carcinoma (SCC); however, conventional preoperative imaging has demonstrated sensitivities below 60% for sub-centimeter metastases, resulting in treatment misallocation for approximately 20–30% of patients.PurposeThis study aimed to develop and validate a minimal gene expression signature that can be performed on routine biopsy specimens to predict preoperative LNM in cervical SCC.MethodsThis retrospective biomarker discovery and validation study had a two-phase design. In the discovery phase, we analyzed transcriptomic data from 116 The Cancer Genome Atlas (TCGA) cervical SCC samples and identified differentially expressed genes (DEGs) using Benjamini–Hochberg (BH) false discovery rate correction (FDR < 0.10). Then, we refined them using the least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate logistic regression analysis. The locked signature was independently validated in a prospectively collected cohort of 202 patients (101 LNM-positive patients and 101 LNM-negative patients) from the Fudan University Shanghai Cancer Center using quantitative reverse transcription–polymerase chain reaction (qRT-PCR), with histopathological lymphadenectomy confirmation as the reference standard. Performance was assessed based on area under the curve (AUC), sensitivity, specificity, predictive values, and bootstrap internal validation. Decision curve analysis and a combined molecular-clinical model were also evaluated.ResultsOf the 231 DE genes, a three-gene signature (LOC494141, GLOD5, and GML) was identified by sequential filtering. In the independent validation cohort, the signature achieved an AUC of 0.745 (95% CI: 0.676–0.814), with a sensitivity of 62.38%, a specificity of 64.36%, a positive predictive value of 63.64%, and a negative predictive value of 63.11%. Bootstrap validation confirmed model robustness (optimism-corrected AUC: 0.722; calibration slope: 0.913; Hosmer–Lemeshow p = 0.387). A combined model integrating the signature with tumor size and lymphovascular space invasion achieved an AUC of 0.789 (95% CI: 0.724–0.854), with a significant incremental value [net reclassification improvement (NRI) = 0.42, p = 0.001; integrated discrimination improvement (IDI) = 0.065, p < 0.001]. Decision curve analysis demonstrated net clinical benefit across threshold probabilities of 20–70%. At a 20% population prevalence, the adjusted negative predictive value reached 87.3%.ConclusionThis three-gene expression signature provides clinically informative preoperative risk stratification for LNM in cervical SCC. Intended as a complementary tool within integrated clinical assessment frameworks rather than a standalone diagnostic tool, this affordable qRT-PCR-based assay holds particular promise for resource-limited settings, pending prospective multicenter validation.